With increasing age and/or as a consequence of certain diseases, the body's soft tissues, including collagen, muscle and fat can diminish, affecting appearance and/or diminishing function. With age, facial skin begins to show the effects of gravity, sun exposure and years of facial muscle movement, such as smiling, chewing and squinting. The underlying tissues that keep skin looking youthful and plump begin to break down, often leaving laugh lines, smile lines, crow's feet or facial creases over the areas where this muscle movement occurs. Areas surrounding the eyes, the temple and cheeks can become sunken and hollow in appearance. Internally, sphincter muscles that control many of the body's autonomic functions such as control of bladder function and gastric reflux diminish with age or disease. A number of medical filler products and techniques have been developed in an effort to correct these soft tissue deficits and restore form and function.
Soft-tissue fillers, most commonly injectable collagen or autologous fat, can help fill in tissue deficits, temporarily restoring a smoother, more youthful-looking appearance to the skin. When injected intra-dermally, these fillers plump up and add fullness to creased and sunken areas of the face. Injected collagen and fat are primarily used to improve the appearance of the skin's texture. They can help fill out deep facial wrinkles, creases and furrows, “sunken” cheeks, skin depressions and some types of scars. They are also used to add a fuller, more youthful look to the lips.
Deep folds in the face or brow caused by overactive muscles or by loose skin may be more effectively treated with cosmetic surgery, such as a facelift or browlift. Injectables are sometimes used in conjunction with facial surgery procedures, as injectables alone typically cannot change facial contours as can surgery.
Injectable bovine collagen received approval from the Food and Drug Administration in 1981 and was the first injectable filler product to be marketed in the United States. Allergic reaction is the primary risk of bovine collagen injections. Collagen injections should be used with caution in anyone with a history of allergies, and skin tests must be performed a month before the procedure to help determine if the patient is allergic to the substance. The collagen is injected using a fine needle inserted at several points along the edge of the treatment site. Since part of the substance is saline that will be absorbed by the body within a few days, the doctor will slightly overfill the area. Risks not necessarily related to allergies include infection, abscesses, open sores, skin peeling, scarring and lumpiness, which may persist over the treated area.
Collagen's longevity depends on the patient's lifestyle and physical characteristics as well as the part of the body treated. In general, the injected material is likely to disappear faster in areas that are more affected by muscle movement. The injections may need to be repeated at intervals of six months or longer to maintain the maximum cosmetic effect.
Collagen injections are also used as a treatment for stress urinary incontinence resulting from an incompetent sphincter mechanism. When implanted at the bladder neck, this filler acts as a soft bulking material augmenting the natural function of the sphincter mechanism, thus helping to restore urinary continence. However, patients may require retreatments to maintain continence.
The fat-injection procedure, known as autologous fat transplantation or microlipoinjection, involves extracting fat cells from the patient's abdomen, thighs, buttocks or elsewhere and reinjecting them beneath the facial skin. Fat is most often used to fill in “sunken” cheeks or laugh lines between the nose and mouth, correct skin depressions or indentations, minimize forehead wrinkles and enhance the lips.
Fat injections offer two advantages over bovine collagen. Fat cells are living cells which are transplanted from one area of the body to the site where they are being injected. Once the cells are implanted they continue to live and do not break down as quickly or dramatically as collagen protein does. Also, as the injected fat is taken from the patient's own body, there is no chance of an allergic reaction to the injection. Additionally, a relatively larger volume (50-100 cc) of fat cells may be transplanted, to augment sunken areas of the face, including the temples and cheeks.
The disadvantage of fat injection lies in the transplant process. Fat cells removed from one area and transplanted to another suffer damage in transit, and may not find adequate blood supply at the new site in order to survive. It is estimated that one half to two thirds of the fat cells transplanted to the new site die and are absorbed by the body. Therefore, not only must two to three times the amount of material needed be injected into the new site (in order to insure that one third of the required amount properly implants), but the procedure must be repeated two to three times in order to get the correct amount at the site. While fat injections offer longer lasting results than bovine collagen, the building up process takes longer. In addition, the disruption caused to the area treated (because of the larger amounts of material being injected) can cause swelling, bumpiness and discoloration for three to five days following each treatment.
Injectable products can also be prepared from the patient's own collagen and/or fibroblast cells, or from donated cadaver dermis. These materials function similarly to bovine products but avoid the risk of allergic reactions. Tissue donors are typically screened for absence of transmissible diseases; however, there is still some risk of transmitting viral diseases, including the human immune deficiency virus, with these products.
A number of other biological filler materials have been developed for facial-rejuvenation purposes. These include a porcine gelatin powder compound that is mixed with a patient's own blood and injected to plump up the skin (similar to injectable collagen) and non-animal derived hyaluronic acid (a substance found in all living organisms). The porcine preparations have uncertain results, high antigenicity due to utilization of animal-origin components, and risk of infection via blood application. In contrast, the hyaluronic acid products do not cause allergic reactions, but only last three to six months
A number of synthetic products have been developed to overcome the inherent risks of biologics. Synthetic products may include non-biodegradable components, such as expanded polytetrafluoroethylene (“ePTFE”), polymethylmethacrylate (“PMMA”), polydimethylsiloxane (“PDMS”), and polyacrylamide. These materials do not readily break down in the body, and are therefore permanent. The body mounts a foreign body response to these polymers and forms a tight fibrous capsule around the material. Risks include the potential for these materials to migrate away from the injection site or to form an inclusion cyst at the site of encapsulation. The FDA has banned the use of liquid silicone in the U.S as a filler material, due to risks of migration and the potential to stimulate autoimmune disorders. Non-biodegradable injectables have been problematic in the treatment of urinary incontinence due to migration of the particles.
Another approach to providing a highly biocompatible synthetic filler material that will not migrate or encapsulate is to utilize biodegradable polymers. Biodegradation has been accomplished by synthesizing polymers that have hydrolytically unstable linkages in the backbone. Common chemical functional groups with this characteristic are esters, anhydrides, orthoesters, and amides. As of 1960, a wide range of biodegradable synthetic polymers had been developed, including a number of polymers derived from natural sources such as modified poly-saccharides (cellulose, chitin, and dextran) or modified proteins (fibrin and casein).
Some commercially available biodegradable devices are polyesters composed of homopolymers or copolymers of glycolic and lactic acid. Copolymers of glycolic acid with both l-lactic and d,l-lactic acids have been developed for both device and drug delivery applications. Medical devices comprised of these polymers have been used in wound closure (sutures, staples); tissue screws; orthopedic fixation devices (pins, rods, screws, tacks, ligaments); dental applications (guided tissue regeneration, such as products for gums and regeneration of maxillary bone); cardiovascular applications (stents, grafts); intestinal applications (anastomosis rings); and applications systems for repairing meniscus and cartilage. Some biodegradable polymers have also been used for cosmetic wrinkle patches. A widely used device is a copolymer of 90% glycolic acid and 10% l-lactic acid, developed by Ethicon as an absorbable suture material under the trade name Vicryl™. It absorbs within three to four months but has a slightly longer strength-retention time.
One of the first bioactive degradable polymers approved by the FDA was polylactide-co-glycolide acid. The implant based on this polymer is a slow dissolving injectable device for treatment of advanced prostate cancer. This device uses biodegradable a mixture of poly-glycolic acid (25%) and poly-lactic acid (75%) in the form of microspheres to gradually release an acetate for periods of up to 4 months, thereby avoiding the need for daily injections.
Other products have also been approved such as ProLease® and Medisorb®, medical devices for the creation of slowly dissolving (from a few days up to several months) injectable products. Both technologies consist of injection methods comprised by bioactive molecules integrated in a matrix of poly-d,l-lactide-co-glycolide.
The use of biodegradable homopolymers and co-polymers of glycolic and lactic acid as injectable bulking implants is also disclosed in Australian patent no. 744,366. This patent discloses the purported use of polymeric lactic acid microspheres, having a mean diameter ranging from 5μ to 150μ, suspended in a gel. According to this invention, glycolic acid repeat units may be incorporated into a lactic co-glycolic acid polymer, to influence rates of degradation.
However, a major obstacle to the use of the aforementioned biodegradable polymers as an injectable bulking agent or implant is that, due apparently to surface charge characteristics, the polymeric particles tend to aggregate prior to and/or during clinical application. This aggregation causes the products to be difficult to mix following reconstitution—mixing often requiring an ancillary laboratory device, such as a Vortex mixer, to adequately suspend the microparticles. Further, despite aggressive mixing, the polymeric particles will frequently aggregate and obstruct and clog the syringe and needle, resulting in product wastage and/or suboptimal product injection. If injected in aggregated form, the polymers may not infiltrate within the interstitial spaces in the body or be assimilated and degraded thereby in an optimal manner. Instead, the aggregated particles may form hard, insoluble nodules at the injection site, causing edema and swelling, and requiring corrective medical intervention. In addition, products, based on polylactic acid, intended to replace fat loss at the temples and/or cheeks are expensive for this purpose, as the procedure requires several interventions—from three to six, 25 to 30 days apart.
Glycolic acid monomer (GA), in solution, is present in a wide number of cosmetic products and its use as a biomaterial has been suggested for pathologies related to an increase in corneocyte cohesion. GA has been used for acne prevention and treatment, as a component of topicals and injectable solutions. GA is also believed to reduce inflammation and optimize moistening. (It is documented that glycolic acid produces a 300% increase in skin moisture.) Despite its beneficial hydrating and intracellular diffusive properties, to date, no injectable implants have been prepared containing GA, alone or in combination with a polymeric filler.
In summary, the injectable products in the art are characterized by very short duration periods and/or allergic reaction. In addition, some of their components are dangerous and even lethal. Biodegradable polymeric implants that overcome some of these drawbacks suffer from further application complications such as needle clogging and nodule formation.
Thus, it would be desirable to design an implant that degrades very slowly over time; will not cause allergic reaction, rejection, or infection; does not require surgery to remove damaging residues or nodules; and will not migrate to the lungs, kidneys, liver, or other parts of the human body with deleterious results. For injectable applications, an implant having superior flow properties which avoids aggregation, needle clogging and nodule formation is. also desired.